Causative Genes In Neurodegeneration

Neurodegenerative diseases include a lot of different pathological conditions of specific areas of the central nervous system (CNS), characterized by the progressive loss of neuronal tissues.

Alzheimer's disease (AD), characterized clinically by the impairment of cognitive functions and changes in behavior and personality, is the most common form of dementia in the elderly affecting several million patients worldwide. There are two pathological hallmarks of AD leading to neuronal loss in the brain: the occurrence of extracellular senile plaques, or amyloid plaques, and the presence of intracellular neurofibrillary tangles of hyperphosphorylated tau protein (1). Genetically, AD is complex: rare, fully penetrant mutations in three genes have been identified to date in families with early-onset (< 65 years) autosomal dominant AD (EOAD), whereas the majority of AD cases (90-95%) are nonfamilial sporadic late onset (> 65 years) forms (LOAD); however, epidemiological studies indicate that about 30% of AD patients have a family history of disease, indicating the existence of numerous LOAD susceptibility loci. To date, more than 150 mutations have been identified in the three causative genes of early onset AD: a link between AD and a missense mutation of the amyloid precursor protein gene (APP), which maps to chromosome 21q21.2 was identified in 1991 (2). Several APP mutations have been subsequently found to be the cause of some early-onset-inherited AD in different families: all of them are situated at or near a, P, or y secretase sites and alter APP proteolysis. The normal function of APP is still unknown, however, amyloid plaques contain small toxic cleavage products of the amyloid precursor protein, denoted as P-amyloid (AP) peptides AP40 or AP42. Since 1995, the presenilin 1 gene (PS1) has been associated with EOAD (3), and more than 120 different mutations have been discovered in the PS1 gene. The gene maps on chromosome 14q24.3 and encodes an integral membrane protein with eight transmembrane domains. The presenilin 2 gene (PS2) on chromosome 1q31-q42 encodes for an integral transmembrane protein that has overall homology of 67% with the amino acid sequence of the PS1 protein, and since 1995 (4,5), several missense mutations in the PS2 gene have been identified in EOAD families. Presenilins facilitate

Oxidative Stress and Neurodegenerative Disorders Edited by G. Ali Qureshi and S. Hassan Parvez

© 2007 Elsevier B.V. All rights reserved.

the cleavage of APP, y-secretase cleavage, which generates Aß peptides. The APP and presenilin gene mutations activate ß- and y-secretases leading to a common consequence of an increased generation of Aß peptides, which subsequently aggregate to form the neu-ritic plaque in the AD patients' brain (an updated overview of AD causative mutations can be found at the Alzheimer Disease and Frontotemporal Dementia Mutation Database: (http://www.molgen.ua.ac.be/admutations/)). Surprisingly, mutations in the APP and presenilin genes do not account for LOAD, whose aetiology is complex and probably due to the interaction between susceptibility genes and environmental factors. Another approach to the aetiology of AD takes as a starting point the abnormal accumulation of the paired helical filaments (PHF) or neurofibrillary tangles in the neurons of AD individuals. PHF are composed predominately of hyperphosphorylated form of the protein tau. Tau is a microtubule-associated protein that binds to microtubules and promotes their assembly. Filamentous tau protein deposits are also the defining characteristic of other neurodegen-erative diseases, many of which are frontotemporal dementias or movement disorders, such as Pick's disease, progressive supranuclear palsy, and corticobasal degeneration. Six tau isoforms are produced in adult human brain by alternative mRNA splicing from a single gene, and for many years there was no evidence implicating Tau mutations in the neurodegenerative process; however the discovery of mutations in the Tau gene in a form of frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) has shown that dysfunction of tau protein causes neurodegeneration (6); at present more than 30 different Tau mutations have been described in families with FTDP-17, some of them affecting the pre-mRNA splicing, and others with an effect at RNA or protein levels (an updated overview can be found at the Alzheimer Disease and Frontotemporal Dementia Mutation Database: (http://www.molgen.ua.ac.be/admutations/)).

Parkinson's disease (PD) is the second most common neurodegenerative disorder after AD, and is characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN), which leads to progressive movement impairments; evidence for the existence of a genetic component in PD is supported by epidemiological and positron emission topography (PET) studies in familial kindred and monozygotic and dizygotic twins (7). In a minority of cases, PD is inherited as a Mendelian autosomal dominant or recessive trait. Studies in these families have identified several causative genes (a-synuclein, parkin, UCH-L1, PINK1, DJ-1 and NR4A2) and other loci of linkage across the genome (PARK3, PARK8, PARK9, and PARK10) pending characterization and/or replication. A mutation in exon 4 of the a-synuclein gene (known as PARK1) causing an Ala53 ^ Thr substitution in the protein was found to segregate with the disease in an Italian-American kindred and three Greek kindreds (8). Another mutation in the PARK1 gene, leading to an Ala30 ^ Pro substitution, was subsequently described in a German kindred (9). An a-synuclein locus triplication (PARK4) has been recently found as being causative of PD in a large family (10). Another pathological mark of PD is the formation of Lewy bodies (LB), cytoplasmic inclusions which are present in the dopaminergic neurons of the SN and other regions of the brain. Although a-synuclein mutations are only a rare genetic cause in PD, a-synuclein is the major fibrillar component of LB and conformational abnormalities leading to aggregation, and deposition of proteins are a common feature of neurodegeneration in several related disorders (7). The detection of an Ile93 ^ Met mutation in the ubiquitin carboxy-terminal hydrolase L1 gene (UCH-L1 or PARK5) in a German family with autosomal dominant PD (11) leads to the idea that an impaired proteasomal degradation of abnormal proteins may underlie the pathogenesis of PD. Autosomal-recessive juvenile Parkinsonism (AR-JP) is characterized by early-onset (< 40 years) and a marked response to levodopa treatment. The genetic locus for AR-JP was identified in Japanese families, which led to identification of homozygous deletions in the parkin gene (PARK2) on chromosome 6q25.2-q27 (12). In addition to the two homozygous exon deletions first detected in four Japanese families, several other groups have reported exon deletions and mutations in the PARK2 gene that result in protein truncation or amino acid substitution (7). Even if the function of parkin is still unknown, the homologies to ubiquitin suggest a role in the mediation of proteasomal degradation of proteins. Abnormalities in proteasomal degradation may cause the aberrant accumulation of proteins as is indicated by the presence of poly-ubiquitinated proteins in the LB, however LB are absent in parkin PD patients, suggesting a different mechanism of neurodegeneration (12). Mutations in the PTEN-induced putative kinase 1 (PINK-1 or PARK6), a protein whose loss of function is supposed to render neurons more vulnerable to cellular stress, have been recently related with autosomal recessive, early-onset PD (13). Mutations in the DJ-1 gene (PARK7), whose function is supposed to be related to the oxidative stress response, have been associated with a monogenic early-onset autosomal recessive form of Parkinsonism characterized by slow progression and response to levodopa (14). It is currently unclear whether or not LB are present in brains of individuals bearing PARK-6 or PARK-7 mutations. Moreover, mutations in a nuclear receptor of subfamily 4 gene (NR4A2) located on 2q22, which does not map to any of the known PD linkage regions, and is involved in the differentiation of dopaminergic cells, have been recently associated with PD (15). Unlike familial PD, the heritability of sporadic PD is probably low, with an increased contribution of gene-environment interactions.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease, where neurodegeneration affects primarily, although not exclusively, motor neurons of the cerebral cortex, brain stem, and spinal cord, leading ultimately to paralysis and premature death (16). Ten percent of amyotrophic lateral sclerosis cases are of familial origin, and the cytosolic copper-zinc superoxide dismutase gene (SOD1) was the first ALS gene (ALS1) for an autosomal dominant form of familial ALS (FALS), and was mapped to chromosome 21q21 (17). More than 100 SOD1 mutations have been described, accounting approximately for 2% of all ALS and 20% of familial cases (18). Autosomal recessive familial amyotrophic lateral sclerosis (RFALS) is rare but has been reported in settings of high consanguinity such as Tunisia. The locus for RFALS maps to chromosome 2q33 (ALS2), and the gene was recently identified and named alsin (19,20). An overview of ALS mutations can be found at the ALS online database: (http://www.alsod.org.); moreover at least six other loci for FALS have been identified by means of linkage analysis (18).

An heterogeneous group of neurodegenerative disorders is caused by trinucleotide repeat expansion in the causative gene; among them Huntington's disease (HD), den-tatorubral pallidoluysian atrophy (DRPLA), spinobulbar muscular atrophy (SBMA) and the spinocerebellar ataxia types 1-3, 6, 7, and 12 (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA12) result from a CAG trinucleotide repeat expansion which is translated into a poly-glutamine stretch in the respective protein and share a dominant pattern of inheritance (21). All the genes involved in the earlier mentioned polyglutamine disorders have been mapped and for each of them, the CAG repeat length ranges in a permitted interval in the normal population, while is expanded in people affected by the disease (21). For example HD

Table 1. Causative genes for neurodegenerative diseases

Gene

Disease

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